tbuckley/cabot-search huggingface dataset:
DCK expression by RNAseq as a potential biomarker of gemcitabine response in sarcoma.
Authors: David A. Liebner, Erin A Fetzer, Marium Husain, James Lin Chen, Gabriel Tinoco
Journal: Journal of Clinical Oncology (2023)

11578 Background: Deoxycytidine kinase (DCK) is responsible for activation of gemcitabine by phosphorylation of gemcitabine to its monophosphate form. Studies have suggested that DCK expression may be correlated to response to gemcitabine in various solid tumors, and that downregulation of DCK may be at least partly responsible for gemcitabine-resistance in vitro. However, the significance of DCK expression in sarcomas as a biomarker of response to gemcitabine remains poorly characterized. Methods: Participants enrolled in the prospective Electronic Health Record (EHR)-Based Comprehensive Bone and Soft Tumor Registry ( NCT02677961 ) at The Ohio State James Cancer Center who had received gemcitabine-based chemotherapy for the treatment of bone and soft tissue sarcoma were eligible for this study. A total of 179 patients were identified who had received at least one cycle of gemcitabine-based chemotherapy, between January 1st, 2014, to December 31 st , 2022. Whole exome RNASeq expression data was available for 36 of these patients who had received gemcitabine-based chemotherapy in the setting of active disease. Results: Of the 36 patients included in this study, 22 were female and 14 were male. Nine different main disease types were identified in the patient subset. These include angiosarcoma (8), chondrosarcoma (1), leiomyosarcoma (16), liposarcoma (3), malignant peripheral nerve sheath tumor (1), myxofibrosarcoma (2), osteosarcoma (2), undifferentiated pleomorphic sarcoma (3), and undifferentiated spindle cell sarcoma (1). The median time to treatment discontinuation (TTD) among all patients was 178 days. Among DCK low-expressors (n = 16), the median TTD was 86 days; among high-expressors (n = 16), the median TTD was not reached. Differences between groups did not reach statistical significance (HR = 0.55, p = 0.14). Conclusions: DCK expression by clinical RNASeq is a potential biomarker of gemcitabine-response in sarcoma, but larger studies are necessary to evaluate the potential clinical significance and possible role of DCK expression in identifying patients most likely to benefit from gemcitabine-based chemotherapy.
Immune checkpoint inhibitor effects on male reproduction.
Authors: Sally Leong, Christina Wang, Mykola Onyshchenko, Preethi Ilangovan, Adam Rock, Michael Shodiya, Ronald Swerdloff, Steve Yoon, Andrew G. Gianoukakis
Journal: Journal of Clinical Oncology (2023)

e16528 Background: Immune checkpoint inhibitors (ICI) have been shown to improve overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) as compared to previous therapy with multi-kinase inhibitors (MKI). However, little is known about the effects of these drugs on male reproductive capacity and the current data regarding effects of MKI and ICI therapies on gonadal function and fertility are both limited and conflicting. We sought to evaluate effects of MKI and ICI on male reproductive function in patients with RCC. Methods: Male patients with RCC receiving MKI or ICI for a period of at least 3 months were identified. Inclusion criteria included age ≤ 50 years, no prior history of chemotherapy, and no prior history of medical or surgical conditions that would affect spermatogenesis such as hypogonadism, Klinefelter syndrome, or vasectomies. Patients were instructed to abstain from ejaculation 2 to 7 days prior to study collection. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), morning testosterone, and a semen analysis was obtained for each patient and analyzed. Results: Of 10 patients, 5 (50%) were on ICI and 5 (50%) were on MKI. Of the patients on ICI, 2 (40%) exhibited abnormal semen morphology, motility, and sperm concentration. Of the patients on ICI, one exhibited elevated LH and FSH levels and one exhibited elevated LH levels only. Of the patients on MKI, 2 (40%) exhibited abnormal semen morphology, motility, and sperm concentration. One patient on MKI exhibited elevated LH and FSH levels. All patients had normal testosterone levels. Conclusions: Our preliminary descriptive data analysis suggests that both ICI and MKI may affect semen morphology and motility, sperm concentration, and LH and FSH levels, but does not affect testosterone levels. Due to the currently limited sample size, abnormal semen analysis and hormone levels may be attributable to confounding factors, such as performance status, the metastatic disease itself, comorbidities, etc. Study recruitment and analysis are ongoing.
A phase IIb study of selinexor in combination with carfilzomib, daratumumab, or pomalidomide in patients with multiple myeloma relapsing on current therapy.
Authors: Noa Biran, David H. Vesole, Harsh V. Parmar, Pooja Phull, Kimberley Doucette, Rena Feinman, Joshua Zenreich, Palka Anand, Kristin Ivanovski, Monique Pace, Genevieve Breeze, Rania Amer, Lisa Biamonte, Adolfo Aleman, Rashmi Unawane, Elizabeth Pendergrass, Alexandra Della Pia, Susan Kumka, David Samuel DiCapua Siegel
Journal: Journal of Clinical Oncology (2023)

e20042 Background: Selinexor is an oral, selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1), leading to retention of tumor suppressor proteins and apoptosis in malignant cells. Preclinical studies suggest synergistic activity when selinexor is combined with other treatments for MM. We hypothesize the addition of selinexor can recapture response to patients relapsing or refractory on carfilzomib (CFZ), pomalidomide (POM) or daratumumab (DARA)-based regimens. Methods: This is an ongoing phase IIb, open-label, multicenter study to evaluate the safety and efficacy of selinexor plus CFZ, POM, or DARA in patients with MM. Patients were enrolled to each arm only if their disease was refractory to the specific drug of interest (CFZ for Arm 1, POM for Arm 2, and DARA for Arm 3). Arm 1 (n=1) consists of selinexor 80 mg orally on D1, 8, 15; CFZ 56 mg/m2 IV on D1, 8, 15; and dexamethasone (DEX) on D1, 8, 15, 22. Arm 2 (n=7) consists of selinexor 60 mg orally on D1, 8, 15; POM 4 mg orally on D1-21; and DEX on D1, 8, 15, 22. Arm 3 (n=7) consists of selinexor 100 mg orally on D1, 8, 15, 22; DARA 16 mg/kg IV or 1,800 mg SQ on D1, 8, 15, 22 for C1-2; D1 and 15 for C3-6; D1 for ≥C7; and DEX on D1, 8, 15, 22. The primary endpoint is ORR and secondary endpoints include PFS, OS, MRD negativity and TEAEs. Results: At data cutoff (Feb 6 2023), 15 patients were enrolled with a median age of 64 years (range 60-83), 27% with ISS stage III MM, 73% with high-risk cytogenetics, 93% refractory to the last LOT, 47% triple refractory, and 33% quadruple refractory (Table). The ORR was 33% (4/12; 4 PR) and the CBR was 92% (11/12; 7 SD); 3 patients are pending. The most common grade 3-4 TEAEs (n=34) were neutropenia (32%), hypophosphatemia (9%), pneumonia (6%), hyperglycemia (6%), and fatigue (6%). Ten patients discontinued treatment due to PD (n=5), withdrawal of consent (n=2), or TEAEs (n=3; fall, diarrhea, and RSV pneumonia), of whom 1 patient died while hospitalized for diarrhea and weakness. Conclusions: Preliminary results show selinexor plus CFZ, POM, or DARA is safe and restores sensitivity to therapy in relapsed/refractory MM patients. In this population of heavily pretreated MM patients, the ORR (33%) and CBR (92%) observed are higher compared to those seen with single-agent selinexor (ORR 4% and CBR 21%) (Chen C et al, Blood 2018). Clinical trial information: NCT04661137 . [Table: see text]
Peripheral immunological response to treatment with a novel bifunctional anti-PD-L1/TGFβRII agent in recurrent/metastatic nasopharyngeal carcinoma.
Authors: Ngar Woon Kam, Jeffrey Yan Ho Lau, Wei Dai, Chi Leung Chiang, Chi Ming Che, Victor Ho-Fun Lee, Dora Lai Wan Kwong
Journal: Journal of Clinical Oncology (2023)

e14622 Background: Anti-programmed cell death protein-ligand 1 (PD-L1) monotherapy has not shown promising anti-tumor effects in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) in first-line settings. Consequently, second-generation checkpoint inhibitors via targeting multiple pathways are urgently needed. Bintrafusp alfa (also known as M7824) is one of such agents that targets both the transforming-growth factor beta (TGF-β) and PD-L1 pathways. As T cells are the major immune cell subset responsible for tumor destruction, we focus on the peripheral memory T-cell subsets. Through the evaluation of peripheral biomarker analysis and their correlation with clinical outcomes, we have characterized blood-based dynamic phenotypes that predict responses to M7824 in NPC. Methods: Biomarker analysis was performed as part of a phase II clinical trial (NCT04396886) in patients with treatment-refractory histologically confirmed recurrent NPC (n=32) who received M7824. Peripheral blood samples were obtained at baseline before treatment (D0) and every 2 weeks during treatment. Samples collected at D0 and at time of best response assessment (DR) were analysed using multicolor flow cytometry. Patients with complete/partial response or stable disease for at least 6 months were considered responders (R), those with stable disease less than 6 months or progressive disease were considered non-responders (NR). Results: Peripheral T cells between R (n=10) and NR (n=22) patients were compared. While the overall percentage of memory T-cell subsets was similar in both groups after treatment, R patients displayed a significantly lower amount of prototype cell death receptor, CD95, among terminally differentiated effector memory (TEMRA; CD45RA + CD62L + ) T cells (CD45 + CD3 + and CD45 + CD3 + CD4 + : p&lt;0.0001; CD45 + CD3 + CD8 + : p=0.0047) (CD95 DR /RvsNR) as compared to patient in NR group. Besides, reduced expression of CD95 DR on TEMRA CD4 T cells was significantly associated with longer overall survival (OS), regardless of response status (median OS: 16.26 months for patients with lower CD95 levels; median OS: 5.29 months for patients with higher CD95 levels [p &lt; 0.0001]). Notably, we noticed that R patients displayed a lower frequency of CD95-expressing TEMRA at the baseline (CD95 D0 /Rvs NR) as compared to NR group. Conclusions: The apoptotic response of peripheral blood TEMRA CD4 T cells (CD95 DR /R vsNR) may be a useful surrogate biomarker for predicting prognosis to M7824 therapy in NPC. The finding of a lower frequency of CD95 D0 TEMRA in R patients suggesting that CD95 may potentially act as a biomarker for predicting treatment response as well as reveal a possible target for guiding therapeutic strategy for R/M NPC.[Table: see text]
Diagnostic model of low-grade serous ovarian cancer and borderline serous ovarian tumor: Model development and validation based on radiomics.
Authors: Kun Song, Zhongshao Chen, Fang Wang, Jiamin Han
Journal: Journal of Clinical Oncology (2023)

e17534 Background: Evidence to date indicates that there is a close relationship between low-grade serous ovarian cancer (LGSOC) and serous borderline ovarian tumor, but there is a significant difference in prognosis. Preoperative imaging and clinical information to assess the nature of lesions as accurately as possible is beneficial to the surgical management of patients. Methods: A total of 104 patients who underwent CT examination and surgical treatment for pelvic masses in Qilu Hospital of Shandong University from 2013 to 2021 were included in the study, including 25 patients with low-grade serous ovarian cancer, 34 patients with serous borderline ovarian tumor, and 45 patients with serous cystadenoma. Quantitative image features were extracted from CT and combined with clinical information to construct a diagnostic model. The diagnostic performance was evaluated by ROC and AUC. Results: The diagnostic model was constructed by RFECV (recursive feature elimination and cross validation) together with SVM (support vector machine), random forest and XGBoost (eXtreme Gradient Boosting) algorithms, among which the RFECV combined random forest algorithm model showed the optimal accuracy (0.78) and AUC (0.92). Combined with clinical features, a new diagnostic model was constructed again by RFECV and random forest, and the accuracy (0.91) and AUC (0.96) were further improved. Conclusions: Through the combination of CT image-based radiomics and clinical features, the clinical diagnosis model was successfully constructed, which can accurately evaluate and predict the pathological types of patients, and is expected to be used in clinical practice and guide surgical decision-making.
A novel genetic marker of fluoropyrimidine-induced cardiovascular toxicity.
Authors: Claire Palles, Marie Lucas, Katie Watts, Sara Galavotti, Ik Shin Chin, Cameron Campbell, Sarah E W Briggs, Emma Jaeger, David Church, Karen Taylor, Judith Bliss, David Fisher, Ayman Madi, David A. Cameron, Timothy S. Maughan, Ian Tomlinson, Timothy Iveson, David James Kerr, Rachel Kerr, Jeremy Cheadle
Journal: Journal of Clinical Oncology (2023)

3028 Background: Fluoropyrimidine (FP) based adjuvant chemotherapy (5-Fluorouracil and Capecitabine) increases survival of patients with colorectal and breast cancers. However, 1-5 % of patients experience cardiovascular toxicity, which is not explained by variants in the gene encoding dihydropyrimidine dehydrogenase. Methods: We sought genetic determinants of FP-induced cardiovascular toxicity by performing a genome wide association study of NCI-CTCAE graded cardiovascular toxicity using samples from the QUASAR 2 trial (n=759 patients with colorectal cancer (CRC)). Validation studies (n= 5438 patients with CRC and 1478 patients with breast cancer) were performed in the SCOT, COIN and TACT2 trials. The most commonly reported symptoms were chest pain, angina and arrhythmias with 6 patients experiencing myocardial infarctions. Results: rs4904753, mapping to an intron of D-glutamate cyclase (DGLUCY) was genome wide significant in QUASAR 2 (P =4.38 x 10 -16 ) and validated in SCOT, COIN and TACT2 (P&lt;0.0002 in all studies. rs4904753 was associated with levels of expression of DGLUCY in multiple tissues including the atrial appendage. Under a recessive model, 45.3% (61/137) of patients with cardiac toxicity as compared to 10.2% (691/6786) of controls carried both minor alleles (meta-analysis: OR=7.72, 95% CI 5.31-11.22, P=1.03 x 10 -26 ). Conclusions: The sensitivity, specificity, positive predictive value and negative predictive values of testing for two copies of the toxicity associated allele of rs4904753 were 48%, 90%, 8% and 99% respectively. Clinical implementation of testing for this variant has the potential to identify almost half of those at risk of FP-induced cardiovascular toxicity with high specificity, thereby enabling changes to their clinical management. [Table: see text]
Phase 1b/2 trial of pepinemab plus avelumab as second line combination immunotherapy for patients with metastatic pancreatic adenocarcinoma.
Authors: Luis I. Ruffolo, Terrence Lee Fisher, Elizabeth E. Evans, Crystal L. Mallow, Megan Boise, Amber Foster, John E. Leonard, Brian A. Belt, Jen Jen Yeh, Maurice Zauderer, David Linehan, Daniel Mulkerin
Journal: Journal of Clinical Oncology (2023)

TPS4195 Background: Monotherapy with immune checkpoint inhibitors (ICIs) is not effective in metastatic pancreatic adenocarcinoma (PDAC), likely due to the unique immunosuppressive tumor microenvironment (TME) of PDAC, thus safe and novel strategies to overcome resistance and facilitate adaptive immune responses are a major unmet need. Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) promotes tumoral infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs without increasing toxicity. Pepinemab, a SEMA4D blocking antibody, in combination (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC (NCT03268057). Pepinemab is also being evaluated in combo with pembrolizumab in patients with metastatic squamous cell carcinoma of the head and neck (NCT04815720). The principal goals of this proof-of-concept study are to investigate the safety, efficacy, and TME biomarker changes of treatment with the combo of pepinemab plus avelumab in patients with metastatic PDAC. Methods: This single-arm, open-label study (NCT05102721) is evaluating the safety, tolerability, and efficacy of pepinemab in combo with avelumab in patients diagnosed with metastatic PDAC who have either progressed on or are otherwise intolerant to first line chemotherapy. Patients must have received 5FU or gemcitabine-based first line therapy with evidence of intolerance or treatment failure, including progression both during or after completing first-line treatment. Accrual for the Phase 1b portion follows a Bayesian Optimal Interval Design (BOIN), beginning at the highest dose combo; 20 mg/kg pepinemab and 800 mg avelumab Q2W. Phase 2 begins after 16 subjects are enrolled at MTD, permitting a Simon’s two stage assessment of futility prior to closing the Phase 1b period. The primary objective for Phase 1b is tolerability, and the primary objective for Phase 2 is therapeutic efficacy compared to historical second-line systemic chemotherapy. The trial anticipates a total evaluable cohort of 40 subjects and is powered to detect a response rate of 23% or greater, with alpha set at 0.1 and 80% power. Exploratory objectives include robust correlative analysis of immune, stromal, and genomic profiling of baseline and on-treatment tumor biopsies to ascertain mechanisms of treatment response and failure. Patient reported outcomes are incorporated throughout the trial to assess disease specific symptoms associated with pancreatic cancer and cancer cachexia. One patient has been enrolled as of Feb 14, 2023. Clinical trial information: NCT05102721 .
Use of molecular NGS vs single gene testing differs by clinical setting and physician’s specialty in mNSCLC management.
Authors: Katherine Elizabeth Keating, Rachael Victoria Hewitt, Priscila Daniele Daniele Ramos Cirillo, Dave Smart, Inês Abrunhosa Amaral, Tessa Paulien Sandberg, Bethany Michelle Slifko, Jose Luis Alarcon Ruiz, Derry Mae Keeling, Chloe Laura Kennedy, Wendy Moore, Jordan Clark, Susanne Munksted, Howard L. McLeod
Journal: Journal of Clinical Oncology (2023)

e18547 Background: Genomic profiling is an important entrée to Precision Medicine (PM) therapies for treating metastatic non-small cell lung cancer (mNSCLC) with 16 new PM therapies approved since 2018, and 10 advancing from second (2L) to the first (1L) line. However, absent or suboptimal predictive biomarker testing leads to patients not benefiting from appropriate PM treatments (64% inappropriate; Sadik et al., 2022). Disparities in testing practices and perceptions remain when considering Next Generation Sequencing (NGS) versus Single Gene (SG) testing. We hypothesized that testing rates are associated with physician’s specialty/clinical setting, and assessed this in real-world data for USA mNSCLC patients. Methods: The DXRX database contains real-world claims and laboratory data covering 60% of USA mNSCLC population (Surveillance, Epidemiology, and Results program - SEER comparison). NGS and SG testing rates for newly diagnosed (1L) and 2L mNSCLC patients (~186K patients from 2018 to 2021) were evaluated by physician specialty and affiliation (self-populated on National Plan and Provider Enumeration System - NPPES). Oncologists and Pathologists referred 63% and 15% of the patients respectively. Results: Oncologists (ONCs) had higher NGS testing rates than pathologists (PATHs), with double the testing rates in 2L. NGS testing rates were higher in academic vs community settings, regardless of specialty. Conversely PATHs had higher SG testing rates than ONCs, particularly in community settings (Table). NGS testing rates were generally higher in 2L and SG testing higher in 1L. Conclusions: NGS is the optimal molecular testing modality for mNSCLC patients, however, there is a disparity of testing rates across physician specialties and treatment settings in decreasing order: academic ONCs &gt; community ONCs &gt; academic PATHs &gt; community PATHs, who favor SG testing. This could be influenced by turnaround time needs, reimbursement challenges, and/or technology diffusion rate. As most mNSCLC patients are treated in the community setting, efforts are needed to tackle disparities in appropriate testing. [Table: see text]
Discovery and validation of AMBLor as a prognostic biomarker for non-ulcerated cutaneous AJCC stage I/II melanoma.
Authors: Penny Lovat, Tom Ewen, Sebastian Podlipnik, Susana Puig, Josep Malvehy, Priscilla Clark, Claire Lewis, Gyorgy Paragh, Paul Bogner, Sonia Mailer, Grant A. McArthur, Akhtar Husain, Niki Stefanos, Paul Barrett, Marie Labus, Philip Sloan
Journal: Journal of Clinical Oncology (2023)

9573 Background: Cutaneous melanoma incidence continue to increase, with a particular increase in the number of patients diagnosed with thin, &lt; 1mm tumours with reduced probability of recurrence-free survival. The inability of current AJCC staging criteria to identify genuinely low risk subsets of patients with AJCC stage I/II tumours thus emphasises the acute need for credible prognostic biomarkers to stratify patient follow-up based on personalised risk. The combined immunohistochemical (IHC) expression of AMBRA1 and Loricrin (AMBLor) in the epidermis overlying non-ulcerated AJCC stage I melanomas has recently been identified as a prognostic biomarker and valuable pre SLNB test. The aim of the present study was to evaluate the potential for AMBLor as a prognostic biomarker for both AJCC stage I and II non-ulcerated melanoma. Methods: Prospective analysis of AMBLor was performed in two independent retrospective cohorts of non-ulcerated AJCC (8 th edition) stage I and II cutaneous melanomas derived from the USA and Australia (discovery cohort) and Spain and the UK (Validation cohort) following validated automated immune-histological staining and binary scoring analysis to define at risk vs low risk subgroups. Each cohort was powered to represent rates of 10% or up to 20% metastasis for stage I or stage II disease respectively. Results: Data revealed retention of AMBLor in the discovery cohort of 541 melanomas correlated with significantly increased recurrence-free survival (RFS) of 96% compared to 87% for patients with stage I/II melanomas in which AMBLor was lost (P = 0.06; HR 3.6, 95% CI 1.99-6.84, NPV 96%). Subsequent AMBLor analysis in the validation cohort of 303 tumours, further confirmed retention of AMBLor was associated with increased RFS of 98% compared to 81% for patients with stage I/II tumours in which AMBLor was lost (P = 0.01; HR 8.16, 95% CI 3.68-18.07). Conclusions: Collectively data from this multi-international study confirm AMBLor as a prognostic biomarker marker able to identify genuinely low risk subsets of AJCC stage I/II melanomas. Inclusion of AMBLor into clinical melanoma management may therefore aid stratification of patient follow up, enable significant savings on healthcare resources and improve patient anxiety.